1. Field of the Invention
The present invention relates to compounds that inhibit certain integrins, particularly to compounds that inhibit .alpha..sub.v integrins.
2. Description of the Background Art
Integrins are a major family of adhesion receptors. They are produced by most cell types and are a means by which the cell senses its immediate environment and responds to changes in extracellular matrix (ECM) composition. ECM is composed of structural and regulatory molecules, some of which include laminin, collagen, vitronectin and fibronectin, as well as a variety of proteoglycans. These molecules, in cooperation with cell surface receptors, not only provide the basis for structural support, but also contribute to the transmission of biochemical signals from the ECM to the cells interior. Thus, integrins are cell adhesion receptors capable of mediating cell-extracellular matrix and cell-cell interactions. Integrins are implicated in the regulation of cellular adhesion, migration, invasion, proliferation, angiogenesis, osteoclast bone resorption, apoptosis and gene expression (P. C. Brooks, DN&P, 10(8), 456-61, 1997).
The integrin family is composed of 15 .alpha. and 8 .beta. subunits that are contained in over twenty different .alpha..beta. heterodimeric combinations on cell surfaces. Each heterodimers have distinct cellular and adhesive specificities. Integrins bind to extracellular matrix proteins or cell surface molecules through short peptides sequences present in the ligands. Although some integrins selectively recognize a single extracellular matrix protein ligand, other bind to two or more ligands. Several integrins recognize the tripeptide Arg-Gly-Asp (RGD), whereas others recognize alternative short peptide sequences. Combinations of different integrins on cell surfaces allow cells to recognize and respond to a variety of different extracellular matrix proteins (J. A. Varner and D. A. Cheresh, Curr. Opin. Cell Biol., 8, 724-30, 1996).
The .alpha..sub.v -series integrins are a major subfamily of integrins. As well as classically mediating cell attachment and spreading, .alpha..sub.v integrins are implicated in cell locomotion, in ligand-receptor internalization, as virus co-receptors, in management of the extracellular protease cascades and as regulators of tumor progression, angiogenesis and apoptosis. The specificities of the five known .alpha..sub.v -integrins, .alpha..sub.v.beta..sub.1, .alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5, .alpha..sub.v.beta..sub.6 and .alpha..sub.v.beta..sub.8 have been defined and they exclusively recognize ligands via the tripeptide sequence RGD, including vitronectin (.alpha..sub.v.beta..sub.1, .alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5), fibronectin (.alpha..sub.v.beta..sub.1, .alpha..sub.v.beta..sub.5, .alpha..sub.v.beta..sub.6), von Willibrand factor (.alpha..sub.v.beta..sub.3), fibrinogen (.alpha..sub.v.beta..sub.3) and osteopontin (.alpha..sub.v.beta..sub.3) (F. Mitjans, J. Cell. Science, 108, 2825-38, 1995).
In disease, adhesive function is frequently compromised and results in tissue disorder, aberrant cell migration and dysregulation of signaling pathways. It is well known that alterations in the composition and integrity of the ECM can significantly influence cellular behavior, which in turn may have an impact on a number of pathological processes such as tumor neovascularization, restenosis, arthritis, and tumor growth and metastasis. Thus, inhibiting the function of molecules that regulate these cellular events may have significant therapeutic benefit (P. C. Brooks, DN&P, 10(8), 456-61, 1997).
There are at least three major classes of reagents currently being developed as integrin antogonists, and these include antibodies (monoclonal, polyclonal and synthetic) and small synthetic peptides (synthetic cyclic RGD peptides), as well as a family of snake venom-derived proteins termed "disintegrins". The third major group of antagonists includes non-peptide mimetics and organic-type compounds.
Integrin .alpha..sub.v.beta..sub.3, the most promiscuous member of the integrin family, mediates cellular adhesion to vitronecin, fibronectin, fibrinogen, laminin, collagen, von Willibrand factor, osteopontin and adenovirus penton base. Expression of this integrin enables a given cell to adhere to, migrate on, or respond to almost any matrix protein it may encounter.
Integrins of the .alpha..sub.v subfamily are implicated in tumor development. Integrin .alpha..sub.v.beta..sub.3 is minimally, if at all expressed on resting, or normal, blood vessels, but is significantly upregulated on vascular cells within human tumors. In particular, both vertical progression of the primary melanoma and distant metastases are characterized histologically by an increased expression of .alpha..sub.v.beta..sub.3 integrin (B. Felding-Habermann et al., J. Clin. Invest., 89, 2018-22, 1992). A study involving human malignant melanoma, an increasingly prevalent and aggressive skin cancer, reported the use of monoclonal antibodies to block the .alpha..sub.v integrin-ligand interaction which resulted in severely disrupting the development of the tumor (F. Mitjans et al., J. Cell Sci., 108, 2825-38, 1995).
Another important physiological role played by integrin .alpha..sub.v.beta..sub.3 in cancer is within the process of angiogenesis. Angiogenesis, the formation of new blood vessels, allows the cancer to spread and grow. It was shown that blood vessels involved in angiogenesis have enhanced expression of .alpha..sub.v.beta..sub.3 (P. C. Brooks et al., Science, 264, 569-571, 1994; C. J. Drake et al., J. Cell Sci., 108, 2655-61, 1995). It was also shown that preventing the .alpha..sub.v.beta..sub.3 integrin from binding to their ligands caused apoptosis (programmed cell death) in the endothelial cells of newly formed blood vessels and inhibited neovascularization (P. C. Brooks et al., Cell, 79, 1157-64, 1994; M. Christofidou-Solomidou et al., Am. J. Pathol., 151(40), 975-83, 1997; J. Luna, Lab. Invest., 75(4), 563-73, 1996). Thus, antagonists of integrin .alpha..sub.v.beta..sub.3 may provide a powerful therapeutic approach for the treatment of neoplasia or other diseases characterized by angiogenesis.
Another pathological process which involves .alpha..sub.v.beta..sub.3 is coronary restenosis. Surgical trauma and/or injury to blood vessels may lead to the stimulation of smooth muscle cells resulting in an increase migration and proliferation of these cells, which causes an occlusion in the vessel wall and prevents blood flow. Following arterial injury, it was shown that there was early upregulation of integrin .alpha..sub.v.beta..sub.3 at sites of cell accumulation within the vessel wall and that selective blockade of .alpha..sub.v.beta..sub.3 was an effective anti-restenotic strategy (S. S. Srivatsa et al., Cardiovascul. Res., 36, 408-28, 1997).
.alpha..sub.v integrins are especially interesting targets since they are implicated in many metabolic processes, such as angiogenesis, bone resorption, and cellular migration and proliferation. Consequently, antagonists of .alpha..sub.v integrins have great therapeutic potential for diseases such as rheumatoid arthritis, psoriasis, eye diseases (diabetic retinopathy and macular degeneration), restenosis, neointimal hyperplasia, osteoporosis and more particularly against tumors, since they simultaneously strike at the developing tumor and at its blood supply (U.S. Pat. No. 5843906-WO 9736859/GD Searle & Co; EP 854140/Hoechst AG; WO 9733887-WO9637492/Du Pont Merck Pharm Co; WO 9844797-WO 9831359-WO 9818461-WO 9744333-WO 9737655-WO 9532710-WO 9408577).
There is thus a constant need to find other antagonists of .alpha..sub.v integrins in order to provide additional modes of treatments for many diseases that still have no cure. The present invention satisfies this and other need.